Phosphadiazine hcv polymerase inhibitors v

ABSTRACT

Provided herein are phosphadiazine polymerase inhibitor, for example, of any of Formulas V, V′, I″, II″, or Va, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.60/967,237, filed Aug. 31, 2007, the content of which is incorporatedherein by reference in its entirety.

FIELD

Provided herein are phosphadiazine polymerase inhibitor compounds,pharmaceutical compositions comprising the compounds, and processes ofpreparation thereof. Also provided are methods of their use for thetreatment of an HCV infection in a host in need thereof.

BACKGROUND

Hepatitis C virus (HCV) is known to cause at least 80% ofposttransfusion hepatitis and a substantial proportion of sporadic acutehepatitis (Houghton et al., Science 1989, 244, 362-364; Thomas, Curr.Top. Microbiol. Immunol. 2000, 25-41). Preliminary evidence alsoimplicates HCV in many cases of “idiopathic” chronic hepatitis,“cryptogenic” cirrhosis, and probably hepatocellular carcinoma unrelatedto other hepatitis viruses, such as hepatitis B virus (Di Besceglie etal., Scientific American, October, 1999, 80-85; Boyer et al., J.Hepatol. 2000, 32, 98-112).

HCV is an enveloped virus containing a positive-sense single-strandedRNA genome of approximately 9.4 kb (Kato et al., Proc. Natl. Acad. Sci.USA 1990, 87, 9524-9528; Kato, Acta Medica Okayama, 2001, 55, 133-159).The viral genome consists of a 5′ untranslated region (UTR), a long openreading frame encoding a polyprotein precursor of approximately 3011amino acids, and a short 3′ UTR. The 5′ UTR is the most highly conservedpart of the HCV genome and is important for the initiation and controlof polyprotein translation. Translation of the HCV genome is initiatedby a cap-independent mechanism known as internal ribosome entry. Thismechanism involves the binding of ribosomes to an RNA sequence known asthe internal ribosome entry site (IRES). An RNA pseudoknot structure hasrecently been determined to be an essential structural element of theHCV IRES. Viral structural proteins include a nucleocapsid core protein(C) and two envelope glycoproteins, E1 and E2. HCV also encodes twoproteinases, a zinc-dependent metalloproteinase encoded by the NS2-NS3region and a serine proteinase encoded in the NS3 region. Theseproteinases are required for cleavage of specific regions of theprecursor polyprotein into mature peptides. The carboxyl half ofnonstructural protein 5, NS5B, contains the RNA-dependent RNApolymerase. The function of the remaining nonstructural proteins, NS4Aand NS4B, and that of NS5A (the amino-terminal half of nonstructuralprotein 5) remain unknown.

Presently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in about40% of patients (Poynard et al., Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy. However, even withexperimental therapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load (Manns et al, Lancet 2001,358, 958-965; Fried et al., N. Engl. J. Med. 2002, 347, 975-982;Hadziyannis et al., Ann. Intern. Med. 2004, 140, 346-355). Furthermore,research shows that using pegylated interferon and ribavirin to treatpatients with HCV can cause significant side effects, such as alopecia,anorexia, depression, fatigue, myalgia, nausea and prunitus (Ward etal., American Family Physician. 2005, Vol. 72, No. 4; Al-Huthail, TheSaudi Journal of Gastroenterology. 2006, Vol. 12, No. 2, 59-67). Severeweight loss is also reported as a side effect in the interferon-basedtherapy in combination with ribavirin (Bani-Sadr et al., Journal ofViral Hepatitis. 2008, 15(4): 255-260). Thus, there is a clear and unmetneed to develop effective therapeutics for treatment of HCV infection.

SUMMARY OF THE DISCLOSURE

Provided herein are phosphadiazine polymerase inhibitor compounds,pharmaceutical compositions comprising the compounds, and processes ofpreparation thereof. Also provided are methods of the use of thecompounds for the treatment of an HCV infection in a host in needthereof.

In one aspect, provided herein is a compound of Formula V′:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein:

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁴ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl;

R^(4′) is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl;

R⁵ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴ and R⁵ together form a partof a 3-8 membered heterocycloalkyl ring;

R^(5′) is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, oralkynyl;

R^(6′) is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl; or R^(5′) and R^(6′)together form a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl, or heteroaryl ring;

R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹; and

each Y is O or S,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In another aspect, provided herein is a compound of Formula V:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁶ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each n is independently an integer from 1 to 4;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula V, V′, I″, II″,or Va, including a single enantiomer, a mixture of an enantiomeric pair,an individual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof; incombination with one or more pharmaceutically acceptable excipients orcarriers.

Also provided herein is a method for treating or preventing an HCVinfection, which comprises administering to a subject a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula V, V′, I″, II″, or Va, including a single enantiomer, a mixtureof an enantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

Also provided herein is a method for treating, preventing, orameliorating one or more symptoms of a liver disease or disorderassociated with an HCV infection, comprising administering to a subjecta therapeutically effective amount of a compound disclosed herein, e.g.,a compound of Formula V, V′, I″, II″, or Va including a singleenantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Also provided herein is a method for inhibiting replication of a virusin a host, which comprises contacting the host with a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula V, V′, I″, II″, or Va, including a single enantiomer, a mixtureof an enantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

Also provided herein is a method for inhibiting replication of a virus,which comprises contacting the virus with a therapeutically effectiveamount of a compound disclosed herein, e.g., a compound of Formula V,V′, I″, II″, or Va, including a single enantiomer, a mixture of anenantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

Also provided herein is a method for inhibiting the activity of apolymerase, which comprises contacting the polymerase with a compounddisclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

Provided is a compound disclosed herein, e.g., a compound of Formula V,V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use intherapy. Also provided is a compound disclosed herein, e.g., a compoundof Formula V, V′, I″, II″, or Va, or a pharmaceutical compositionthereof, for use in treating or preventing an HCV infection. Alsoprovided is a compound disclosed herein, e.g., a compound of Formula V,V′, I″, II″, or Va, or a pharmaceutical composition thereof, for use intreating, preventing, or ameliorating one or more symptoms of a liverdisease or disorder associated with an HCV infection. Also provided is acompound disclosed herein, e.g., a compound of Formula V, V′, I″, II″,or Va, or a pharmaceutical composition thereof, for use in inhibitingreplication of a virus in a host. Also provided is the use of a compounddisclosed herein, e.g., a compound of Formula V, V′, I″, II″, or Va, ora pharmaceutical composition thereof, for manufacture of a medcicamentfor treating or preventing an HCV infection. Also provided is the use ofa compound disclosed herein, e.g., a compound of Formula V, V′, I″, II″,or Va, or a pharmaceutical composition thereof, for manufacture of amedcicament for treating, preventing, or ameliorating one or moresymptoms of a liver disease or disorder associated with an HCVinfection. Also provided is the use of a compound disclosed herein,e.g., a compound of Formula V, V′, I″, II″, or Va, or a pharmaceuticalcomposition thereof, for manufacture of a medcicament for inhibitingreplication of a virus in a host.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs. In the eventthat there is a plurality of definitions for a term used herein, thosein this section prevail unless stated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject.

The term “host” refers to a unicellular or multicellular organism inwhich a virus can replicate, including, but not limited to, a cell, cellline, and animal, such as human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disease; or reducing a subject's risk of acquiring adisorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a cell, tissue, system, animal, or human, which is being sought by aresearcher, veterinarian, medical doctor, or clinician.

The term “IC₅₀” refers an amount, concentration, or dosage of a compoundthat is required for 50% inhibition of a maximal response in an assaythat measures such response.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,Remington: The Science and Practice of Pharmacy, 21st Edition;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 5th Edition; Rowe et al., Eds., ThePharmaceutical Press and the American Pharmaceutical Association: 2005;and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds.,Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a disorder ordisease. As used herein, “active ingredient” and “active substance” maybe an optically active isomer of a compound described herein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “release controlling excipient” refers to an excipient whoseprimary function is to modify the duration or place of release of anactive substance from a dosage form as compared with a conventionalimmediate release dosage form.

The term “nonrelease controlling excipient” refers to an excipient whoseprimary function do not include modifying the duration or place ofrelease of an active substance from a dosage form as compared with aconventional immediate release dosage form.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical. The term “alkyl” also encompasses both linear andbranched alkyl, unless otherwise specified. In certain embodiments, thealkyl is a linear saturated monovalent hydrocarbon radical that has 1 to20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. In certain embodiments, the alkyl is a linear or branchedsaturated monovalent hydrocarbon radical that has at least 1, 2, 3, 4,5, 6, 7, 8, 9, or 10 carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ alkyl groups are also referred as “lower alkyl.” Examplesof alkyl groups include, but are not limited to, methyl, ethyl, propyl(including all isomeric forms), n-propyl, isopropyl, butyl (includingall isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In certain embodiments, the alkyl may besubstituted.

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substituted.The term “alkylene” encompasses both linear and branched alkylene,unless otherwise specified. In certain embodiments, the alkylene is alinear saturated divalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀),1 to 15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, orbranched saturated divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. In certainembodiments, the alkylene is a linear or branched saturated divalenthydrocarbon radical that has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10carbon atoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylenegroups are also referred as “lower alkylene.” Examples of alkylenegroups include, but are not limited to, methylene, ethylene, propylene(including all isomeric forms), n-propylene, isopropylene, butylene(including all isomeric forms), n-butylene, isobutylene, t-butylene,pentylene (including all isomeric forms), and hexylene (including allisomeric forms). For example, C₂₋₆ alkylene refers to a linear saturateddivalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more carbon-carbon double bonds. Thealkenyl may be optionally substituted, e.g., as described herein. Theterm “alkenyl” also embraces radicals having “cis” and “trans”configurations, or alternatively, “E” and “Z” configurations, asappreciated by those of ordinary skill in the art. As used herein, theterm “alkenyl” encompasses both linear and branched alkenyl, unlessotherwise specified. For example, C₂₋₆ alkenyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propenyl, allyl, propenyl,butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more carbon-carbon doublebonds. The alkenylene may be optionally substituted, e.g., as describedherein. Similarly, the term “alkenylene” also embraces radicals having“cis” and “trans” configurations, or alternatively, “E” and “Z”configurations. As used herein, the term “alkenylene” encompasses bothlinear and branched alkenylene, unless otherwise specified. For example,C₂₋₆ alkenylene refers to a linear unsaturated divalent hydrocarbonradical of 2 to 6 carbon atoms or a branched unsaturated divalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, thealkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C₂₋₂₀),2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms or abranched divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkenylene groups include, but are not limited to, ethenylene,propenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more carbon-carbon triple bonds. Thealkynyl may be optionally substituted, e.g., as described herein. Theterm “alkynyl” also encompasses both linear and branched alkynyl, unlessotherwise specified. In certain embodiments, the alkynyl is a linearmonovalent hydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkynyl groupsinclude, but are not limited to, ethynyl (—C≡CH) and propargyl(—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more carbon-carbon triplebonds. The alkynylene may be optionally substituted, e.g., as describedherein. The term “alkynylene” also encompasses both linear and branchedalkynylene, unless otherwise specified. In certain embodiments, thealkynylene is a linear divalent hydrocarbon radical of 2 to 20 (C₂₋₂₀),2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms or abranched divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkynylene groups include, but are not limited to, ethynylene (—C≡C—)and propargylene (—CH₂C≡C—). For example, C₂₋₆ alkynyl refers to alinear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms.

The term “cycloalkyl” refers to a cyclic saturated bridged ornon-bridged monovalent hydrocarbon radical, which may be optionallysubstituted, e.g., as described herein. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10(C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkylgroups include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, decalinyl, and adamantyl.

The term “cycloalkylene” refers to a cyclic saturated bridged ornon-bridged divalent hydrocarbon radical, which may be optionallysubstituted, e.g., as described herein. In certain embodiments, thecycloalkylene has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms. Examples ofcycloalkylene groups include, but are not limited to, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene,decalinylene, and adamantylene.

The term “aryl” refers to a monocyclic or multicyclic monovalentaromatic group. In certain embodiments, the aryl has from 6 to 20(C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl,and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings,where one of the rings is aromatic and the others of which may besaturated, partially unsaturated, or aromatic, for example,dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).All such aryl groups may also be optionally substituted, e.g., asdescribed herein.

The term “arylene” refers to a monocyclic or multicyclic divalentaromatic group. In certain embodiments, the arylene has from 6 to 20(C₆₋₂₀), from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms.Examples of arylene groups include, but are not limited to, phenylene,naphthylene, fluorenylene, azulenylene, anthrylene, phenanthrylene,pyrenylene, biphenylene, and terphenylene. Arylene also refers tobicyclic or tricyclic carbon rings, where one of the rings is aromaticand the others of which may be saturated, partially unsaturated, oraromatic, for example, dihydronaphthylene, indenylene, indanylene, ortetrahydro-naphthylene(tetralinyl). All such aryl groups may also beoptionally substituted, e.g., as described herein.

The term “heteroaryl” refers to a monocyclic or multicyclic aromaticgroup, wherein at least one ring contains one or more heteroatomsindependently selected from O, S, and N. Each ring of a heteroaryl groupcan contain one or two O atoms, one or two S atoms, and/or one to four Natoms, provided that the total number of heteroatoms in each ring isfour or less and each ring contains at least one carbon atom. In certainembodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to10 ring atoms. Examples of monocyclic heteroaryl groups include, but arenot limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl,oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, andtriazinyl. Examples of bicyclic heteroaryl groups include, but are notlimited to, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl,quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, andtetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include,but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl,acridinyl, phenanthridinyl, and xanthenyl. All such heteroaryl groupsmay also be optionally substituted, e.g., as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monocyclic ormulticyclic non-aromatic ring system, wherein one or more of the ringatoms are heteroatoms independently selected from O, S, or N; and theremaining ring atoms are carbon atoms. In certain embodiments, theheterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. Examplesof heterocyclyl groups include, but are not limited to, pyrrolidinyl,piperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl,piperazinyl, tetrahydropyranyl, and thiomorpholinyl. All suchheterocyclic groups may also be optionally substituted, e.g., asdescribed herein.

The term “alkoxy” refers to an —OR radical, wherein R is, for example,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,each as defined herein. Examples of alkoxy groups include, but are notlimited to, methoxy, ethoxy, propoxy, n-propoxy, 2-propoxy, n-butoxy,isobutoxy, tert-butoxy, cyclohexyloxy, phenoxy, benzoxy, and2-naphthyloxy.

The term “acyl” refers to a —C(O)R radical, wherein R is, for example,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl,each as defined herein. Examples of acyl groups include, but are notlimited to, acetyl, propionyl, butanoyl, isobutanoyl, pentanoyl,hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, dodecanoyl,tetradecanoyl, hexadecanoyl, octadecanoyl, eicosanoyl, docosanoyl,myristoleoyl, palmitoleoyl, oleoyl, linoleoyl, arachidonoyl, benzoyl,pyridinylcarbonyl, and furoyl.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, or iodine.

The term “arylalkyl” refers to an aryl group appended to an alkylradical, such as aryl-(CH₂)—, aryl-CH₂—CH₂—, and aryl-CH₂—CH₂—CH₂—.

The term “heteroarylalkyl” refers to an heteroaryl group appended to analkyl radical, such as heteroaryl-(CH₂)—, heteroaryl-CH₂—CH₂—, andheteroaryl-CH₂—CH₂—CH₂—.

The term “optionally substituted” is intended to mean that a group, suchas an alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene,alkoxyl, cycloalkyl, cycloalkylene, aryl, arylene, heteroaryl, orheterocyclyl group, may be substituted with one or more substituentsindependently selected from, e.g., halo, cyano (—CN), nitro (—NO₂),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —R^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —OCH₂C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(b), —NR^(a)C(O)OR^(b),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(b),—NR^(a)S(O)₂R^(b), —NR^(a)S(O)R^(b)R^(c), —NR^(a)S(O)₂R^(b)R^(c), or—OSi—R^(a)R^(b)R^(c); wherein R^(a), R^(b), R^(c), and R^(d) are eachindependently, e.g., hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,aryl, heteroaryl, or heterocyclyl, each optionally substituted, e.g., asdescribed herein; or R^(b) and R^(c) together with the N atom to whichthey are attached form heterocyclyl or heteroaryl, each optionallysubstituted, e.g., as described herein. The group can be substitutedwith any described moiety, including, but not limited to, one or moremoieties selected from the group consisting of halogen (fluoro, chloro,bromo, or iodo), hydroxyl, amino, alkylamino (e.g., monoalkylamino,dialkylamino, or trialkylamino), arylamino (e.g., monoarylamino,diarylamino, or triarylamino), alkoxy, aryloxy, nitro, cyano, sulfonicacid, sulfate, phosphonic acid, phosphate, or phosphonate, eitherunprotected or protected as necessary, as known to those skilled in theart, for example, as taught in Greene, et al., Protective Groups inOrganic Synthesis, John Wiley and Sons, Second Edition, 1991. As usedherein, all groups that can be substituted in one embodiment are“optionally substituted,” unless otherwise specified.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, or no less than about 94% no less than about95%, no less than about 96%, no less than about 97%, no less than about98%, no less than about 99%, or no less than about 99.5%, no less thanabout 99.8%. In certain embodiments, the compound comprises about 95% ormore of the desired enantiomer and about 5% or less of the lesspreferred enantiomer based on the total weight of the racemate inquestion.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “solvate” refers to a compound provided herein or a saltthereof, which further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

Compounds

Provided herein are compounds which are useful for the treatment of HCVinfection, which, in one embodiment, can have activity as HCV polymeraseinhibitors. Also provided herein are pharmaceutical compositions thatcomprise the compounds, methods of manufacture of the compounds, andmethods of use of the compounds for the treatment of HCV infection in ahost in need of treatment.

In one aspect, provided herein is a compound of Formula V′:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein:

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁴ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl;

R^(4′) is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl;

R⁵ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴ and R⁵ together form a partof a 3-8 membered heterocycloalkyl ring;

R^(5′) is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, oralkynyl;

R^(6′) is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R^(5′) and R^(6′)together form a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring;

R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl; and

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In certain embodiments, each pair of R^(5′) and R^(6′) togetherindependently form a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring. In some embodiments, R^(5′) andR^(6′) together independently form a part of a ring having formula O orP:

where

each * is a bond;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹;

each n is independently an integer from 0 to 1, from 0 to 2, from 0 to3, or from 0 to 4;

each m is independently an integer from 0 to 1, from 0 to 2, or from 0to 3;

each A is independently CR¹⁵R¹⁶ or NR¹⁷;

each A′ is independently CR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S orO;

each R¹⁵ is independently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁶ is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂NR⁸R⁹,—(C₁-C₆ alkyl)-NR^(9′)S(O)₂NR⁸R¹⁰, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁷ is a bond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkylor heteroaryl; and

R¹⁸ is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In certain embodiments, each pair of R^(5′) and R^(6′) togetherindependently forms a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring. In certain embodiments, each pairof R^(5′) and R^(6′) together independently forms a benzo ring havingformula (A):

where

each * is a bond;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹; and

n is an integer from 1 to 4,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In some embodiments, each pair of R^(5′) and R^(6′) togetherindependently form a part of a ring having one of formulae C-L:

where

each * is a bond;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R⁹, —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹;

each n is an integer from 1 to 3; and

each X is independently S, O, NH, or N(C₁-C₆ alkyl)

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In certain embodiments, each n is independently an integer from 1 to 2.In certain embodiments, each n is 1.

In other embodiments, the compound of Formula V′ has the followingformula I″ or II″:

where compounds of formula I″ can exist in the following resonancestructures I″-a, or I″-b:

and compounds of formula II″ can exist in the following resonancestructures II″-a, II″-b, or II″-c:

where

each Y is O or S;

each A is independently CR¹⁸ or N;

each A′ is independently CR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S orO;

each R¹² is independently F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR⁹C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹; each R^(9′) is independentlyhydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl;

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹;

each R¹⁵ is independently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁶ is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂NR⁸R⁹,—(C₁-C₆ alkyl)-NR^(9′)S(O)₂NR⁸R¹⁰, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹⁷ is a bond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkylor heteroaryl;

R¹⁸ is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

m is independently an integer from 1 to 3; and

Z has the following structure:

where

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁴ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl; and

R⁵ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴ and R⁵ together form a partof a 3-8 membered heterocycloalkyl ring, wherein each alkyl, aryl,arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,sulfonyl, or alkyl-cycloalkyl is optionally substituted.

In certain embodiments, each n is independently an integer from 1 to 3.In certain embodiments, each n is independently an integer from 1 to 2.In certain embodiments, each n is 1.

Each compound of Formula V′ may exist in various tautomeric forms.Accordingly, provided herein are tautomeric forms of compounds ofFormula V′, for example, when R⁴ is H, when R^(4′) is H, or when R⁴ andR^(4′) are H. For example, compounds having formula V′ where R⁴ andR^(4′) are H may exist in, but not limited to, the following tautomericforms V′_(a), V′_(b) or V′_(c):

wherein

each R¹ is independently H, alkyl, arylalkyl, heteroarylalkyl, halogen,—NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl,arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

each R⁵ is independently H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴ and R⁵ togetherform a part of a 3-8 membered heterocycloalkyl ring;

each R^(5′) is independently H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰,alkenyl, or alkynyl;

each R^(6′) is independently H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, orR^(5′) and R^(6′) together independently form a part of a 3-8 memberedcycloalkyl, aryl, heterocycloalkyl or heteroaryl ring;

each R¹² is independently F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl; and

each Y is independently O or S.

In one aspect, provided herein is a compound of Formula V:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁶ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each n is independently an integer from 1 to 4;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In some embodiments, provided herein is a compound according to any ofFormulas V, V′, I″, II″, or Va as described herein, or a singleenantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In one aspect, provided herein is a compound of Formula Va:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof; wherein

R¹ is H, alkyl, arylalkyl, heteroarylalkyl, halogen, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;

R⁶ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl;

R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl;

each R¹⁴ is independently H, halogen, alkyl, alkenyl, alkynyl, aryl,heterocyclyl, heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl),—O—(C₁-C₆ alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆ alkylene)-S(O)R^(9′), —O—(C₁-C₆alkyl)-S(O)₂R^(9′), —O—(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R^(9′),—O—(C₁-C₆ alkylene)-S(O)₂R^(9′)—O—(C₁-C₆ alkylene)-NR⁸R⁹, —(C₁-C₆alkylene)-S(O)₂R⁸, —(C₁-C₆ alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆alkylene)-S(O)R⁸, —(C₁-C₆ alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸,—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹;

each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;

each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl;

each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; and

each R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹,

wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl is optionallysubstituted.

In certain embodiments according to Formula V, V′, I″, II″, or Va, eachalkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, or alkyl-cycloalkyl is unsubstituted.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ isalkyl, arylalkyl, or heteroarylalkyl. In certain embodiments accordingto Formula V, V′, I″, II″, or Va, R¹ is C₁₋₆ alkyl. In certainembodiments according to Formula V, V′, I″, II″, or Va, R¹ is2-cyclopropylethyl. In certain embodiments according to Formula V, V′,I″, II″, or Va, R¹ is 3,3-dimethylbutyl. In further embodiments, R¹ hasone of the following structures:

In certain embodiments according to Formula V or Va, R⁶ is H, halo,—OR⁸, —NR⁸R⁹, —C(O)R⁸, alkyl, arylakyl, aryl, or heteroaryl. In otherembodiments according to Formula V or Va, R⁶ is hydrogen or halogen. Insome embodiments according to Formula V or Va, R⁶ is H, I, Cl, F,methyl, isobutyl, t-butyl, phenyl or benzyl. In certain embodimentsaccording to Formula IV or IVa, R⁶ is (S)-tert-butyl. In otherembodiments according to Formula V or Va, R⁶ is F. In certainembodiments according to Formula V or Va, R⁶ is heteroaryl. In furtherembodiments, R⁶ is heteroaryl having one of the following structures:

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹²is F, —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl. In certain embodimentsaccording to Formula V, V′, I″, II″, or Va, R¹² is C₁₋₆ alkoxy. Incertain embodiments according to Formula V, V′, I″, II″, or Va, R¹² ismethoxy. In certain embodiments according to Formula V, V′, I″, II″, orVa, R¹² is ethoxy. In certain embodiments according to Formula V, V′,I″, II″, or Va, R¹² is OH. In certain embodiments according to FormulaV, V′, I″, II″, or Va, R¹² is NH₂. In certain embodiments according toFormula V, V′, I″, II″, or Va, R¹² is —CH2-cyclopropyl, isopropyl,—CH₂CH₂CH₂—C(O)NHCH₃, —CH₂CH₂CH₂—C(O)NH₂, or —CH₂CH₂OCH₃.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹⁴is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl where R⁸, R⁹ andR¹⁰ are as defined herein. In other embodiments according to Formula V,V′, I″, II″, or Va, R¹⁴ is hydrogen. In some embodiments according toFormula V, V′, I″, II″, or Va, R¹⁴ is —NR¹⁰SO₂R⁸ where R⁸ is methyl andR¹⁰ is H or alkyl such as methyl or ethyl. In some embodiments accordingto Formula V, V′, I″, II″, or Va, R¹⁴ is OCH₂C(O)NR⁸R⁹ where each of R⁸and R⁹ is independently H or alkyl.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸ isC₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, orC₁₋₆ alkyl-C₃₋₇ cycloalkylene, each optionally substituted as describedherein. In certain embodiments, R⁸ is C₁₋₆ alkyl, optionally substitutedas described herein. In certain embodiments, R⁸ is C₃₋₇ cycloalkyl,optionally substituted as described herein. In certain embodiments, R⁸is cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R⁸ is C₆₋₁₄ aryl, optionallysubstituted as described herein. In certain embodiments, R⁸ isheteroaryl, optionally substituted as described herein. In certainembodiments, R⁸ is heterocyclyl, optionally substituted as describedherein.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸ isC₁₋₆ alkyl. In certain embodiments according to Formula V, V′, I″, II″,or Va, R⁸ is methyl.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁹ ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄aryl, heteroaryl, or heterocyclyl.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ isalkyl; R⁶ is H, alkyl or halogen; R¹² is —OR⁸; R¹⁴ is H or —NHSO₂R⁸; andeach R⁸ is independently H or alkyl. In certain embodiments according toFormula V, V′, I″, II″, or Va, R¹ is alkyl; R⁶ is halogen; R¹² is —OR⁸;R¹⁴ is H or —NHSO₂R⁸; and each R⁸ is independently H or alkyl. Incertain embodiments according to Formula V, V′, I″, II″, or Va, R¹ isalkyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is H or —NHSO₂R⁸; and each R⁸ isindependently H or alkyl. In certain embodiments according to Formula V,V′, I″, II″, or Va, R¹ is alkyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is H or—NHSO₂Me; and R⁸ is H, methyl or ethyl. In certain embodiments accordingto Formula V, V′, I″, II″, or Va, R¹ is C₁₋₆ alkyl; R⁶ is C₁₋₆ alkyl;R¹² is —OR⁸; R¹⁴ is —NHSO₂R⁸; and each R⁸ is independently methyl orethyl. In certain embodiments according to this paragraph, each alkyl,aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,or alkyl-cycloalkyl is unsubstituted.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ is2-cyclopropylethyl; R⁶ is H, alkyl or halogen; R¹² is —OR⁸; R¹⁴ is H or—NHSO₂R⁸; and each R⁸ is independently H or alkyl. In certainembodiments according to Formula V, V′, I″, II″, or Va, R¹ is2-cyclopropylethyl; R⁶ is halogen; R¹² is —OR⁸; R¹⁴ is H or —NHSO₂R⁸;and each R⁸ is independently H or alkyl. In certain embodimentsaccording to Formula V, V′, I″, II″, or Va, R¹ is 2-cyclopropylethyl; R⁶is F; R¹² is —OR⁸; R¹⁴ is H or —NHSO₂R⁸; and each R⁸ is independently Hor alkyl. In certain embodiments according to Formula V, V′, I″, II″, orVa, R¹ is 2-cyclopropylethyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is H or—NHSO₂Me; and R⁸ is H, methyl or ethyl. In certain embodiments accordingto this paragraph, each alkyl, aryl, arylalkyl, heteroaryl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, or alkyl-cycloalkyl is unsubstituted.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ isalkyl; R⁶ is H, alkyl or halogen; R¹² is —OR⁸; R¹⁴ is H; and R⁸ is H oralkyl. In certain embodiments according to Formula V, V′, I″, II″, orVa, R¹ is alkyl; R⁶ is halogen; R¹² is —OR⁸; R¹⁴ is H; and R⁸ is H oralkyl. In certain embodiments according to Formula V, V′, I″, II″, orVa, R¹ is alkyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is H; and R⁸ is H or alkyl.In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ isalkyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is H; and R⁸ is H, methyl or ethyl. Incertain embodiments according to this paragraph, each alkyl, aryl,arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oralkyl-cycloalkyl is unsubstituted.

In certain embodiments according to Formula V, V′, I″, II″, or Va, R¹ is3,3-dimethylbutyl; R⁶ is H, alkyl or halogen; R¹² is —OR⁸; R¹⁴ is—NHSO₂R⁸; and each R⁸ is independently H or alkyl. In certainembodiments according to Formula V, V′, I″, II″, or Va, R¹ is3,3-dimethylbutyl; R⁶ is halogen; R¹² is —OR⁸; R¹⁴ is —NHSO₂R⁸; and eachR⁸ is independently H or alkyl. In certain embodiments according toFormula V, V′, I″, II″, or Va, R¹ is 3,3-dimethylbutyl; R⁶ is F; R¹² is—OR⁸; R¹⁴ is —NHSO₂R⁸; and each R⁸ is independently H or alkyl. Incertain embodiments according to Formula V, V′, I″, II″, or Va, R¹ is3,3-dimethylbutyl; R⁶ is F; R¹² is —OR⁸; R¹⁴ is —NHSO₂Me; and R⁸ is H,methyl or ethyl. In certain embodiments according to this paragraph,each alkyl, aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, or alkyl-cycloalkyl is unsubstituted.

In certain embodiments, provided herein are the following compoundsaccording to formulae V-1 to V-4:

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible via a low energybarrier, the compound may exist as a single tautomer or a mixture oftautomers. This can take the form of proton tautomerism in the compoundthat contains, for example, an imino, keto, or oxime group; or so-calledvalence tautomerism in the compound that contain an aromatic moiety. Itfollows that a single compound may exhibit more than one type ofisomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of an enantiomeric pair, a racemic mixture,or a diastereomeric mixture. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form. Conventional techniquesfor the preparation/isolation of individual enantiomers includesynthesis from a suitable optically pure precursor, asymmetric synthesisfrom achiral starting materials, or resolution of an enantiomericmixture, for example, chiral chromatography, recrystallization,resolution, diastereomeric salt formation, or derivatization intodiastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-ammo-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula V, V′,I″, II″, or Va and is readily convertible into the parent compound invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent compound. They may, for instance,be bioavailable by oral administration whereas the parent compound isnot. The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharncjad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compound provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. For an example, a compoundof Formula V can be prepared as shown in Scheme 1.

In certain embodiments, substituted aldehyde 1A can be reacted withsubstituted hydrazine hydrochloride in the presence of, for example,diethyl ether and triethylamine to form compound 1B. Compound 1B can becoupled with ethyl acetate in the presence of, for example, pyridine, toform compound 1C. Compound 1C can be reacted with, for example, aceticacid, tetrahydrofuran, and sodium cyanohydridoborate to form compound1D. Compound 1D can be coupled with cyanoacetic acid in the presence of,for example, a coupling agent, to form compound 1E. Compound 1E can becyclized by potassium tert-butoxide in the presence of tert-butanol toform cyclic compound 1F. Cyclic compound 1F can be coupled with compound1J in the presence of, for example, trimethylaluminum (AlMe₃), dioxane,and dimethylacetamide (DMA) at 160° C., to form compound 1G. The ethylgroup can be removed from the phosphadiazine group of compound 1G toyield hydroxyphosphadiazine compound 1H. Hydroxyphosphadiazine compound1H can be coupled with a variety R_(D) compounds to form furtherphosphadiazine derivatives 1I, such as aminophosphadiazine compounds.Protecting groups can be used where suitable according to the judgmentof one of skill in the art.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising a compoundprovided herein as an active ingredient, including a single enantiomer,a mixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a pharmaceutically acceptable vehicle,carrier, diluent, or excipient, or a mixture thereof; in combinationwith one or more pharmaceutically acceptable excipients or carriers. Incertain embodiments, the pharmaceutical composition comprises at leastone release controlling excipient or carrier. In certain embodiments,the pharmaceutical composition comprises at least one nonreleasecontrolling excipient or carrier. In certain embodiments, thepharmaceutical composition comprises at least one release controllingand at least one nonrelease controlling excipients or carriers.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein, one ormore other active ingredients. The pharmaceutical compositions thatcomprise a compound provided herein may be formulated in various dosageforms for oral, parenteral, and topical administration. Thepharmaceutical compositions may also be formulated as a modified releasedosage form, including delayed-, extended-, prolonged-, sustained-,pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Deliver Technology,Rathbone et al., Eds., Drugs and the Pharmaceutical Science, MarcelDekker, Inc.: New York, N.Y., 2003; Vol. 126).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise a compound providedherein, including a single enantiomer, a mixture of an enantiomericpair, an individual diastereomer, or a mixture of diastereomers thereof;or a pharmaceutically acceptable salt, solvate, or prodrug thereof; andone or more pharmaceutically acceptable excipients or carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise a compoundprovided herein, including a single enantiomer, a mixture of anenantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof; and one or more pharmaceutically acceptableexcipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, which comprise a compoundprovided herein, including a single enantiomer, a mixture of anenantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof; and one or more pharmaceutically acceptableexcipients or carriers.

The pharmaceutical compositions provided herein may be provided inunit-dosage forms or multiple-dosage forms. Unit-dosage forms, as usedherein, refer to physically discrete units suitable for administrationto human and animal subjects and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of unit-dosage forms include ampoules, syringes, andindividually packaged tablets and capsules. Unit-dosage forms may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofmultiple-dosage forms include vials, bottles of tablets or capsules, orbottles of pints or gallons.

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also include buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsprovided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction, such as drotrecogin-, and hydrocortisone.

B. Parenteral Administration

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including such as lard, benzoinatedlard, olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerinated gelatin. Combinations ofthe various vehicles may be used. Rectal and vaginal suppositories maybe prepared by the compressed method or molding. The typical weight of arectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes may beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. The pharmaceutical compositions inmodified release dosage forms can be prepared using a variety ofmodified release devices and methods known to those skilled in the art,including, but not limited to, matrix controlled release devices,osmotic controlled release devices, multiparticulate controlled releasedevices, ion-exchange resins, enteric coatings, multilayered coatings,microspheres, liposomes, and combinations thereof. The release rate ofthe active ingredient(s) can also be modified by varying the particlesizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate,and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol, organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates may be made by the processes know to those skilled inthe art, including wet-and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

Methods of Use

Provided herein are methods for treating or preventing a hepatitis Cviral infection in a subject, which comprises administering to a subjecta therapeutically effective amount of a compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the subject is a mammal. In another embodiment, the subjectis a human.

Additionally, provided herein is a method for inhibiting replication ofa virus in a host, which comprises contacting the host with atherapeutically effective amount of the compound of Formula V, V′, I″,II″, or Va, including a single enantiomer, a mixture of an enantiomericpair, an individual diastereomer, or a mixture of diastereomers thereof;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Inone embodiment, the host is a cell. In another embodiment, the host is ahuman cell. In yet another embodiment, the host is a mammal. In stillanother embodiment, the host is human.

In certain embodiments, administration of a therapeutically effectiveamount of a compound provided herein, including a single enantiomer, amixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 99% or more reduction in the replication of thevirus relative to a subject without administration of the compound, asdetermined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days,or 30 days after the administration by a method known in the art, e.g.,determination of viral titer.

In certain embodiments, administration of a therapeutically effectiveamount of a compound provided herein, including a single enantiomer, amixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25,50, 75, 100-fold or more reduction in the replication of the virusrelative to a subject without administration of the compound, asdetermined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days,or 30 days after the administration by a method known in the art.

In certain embodiments, administration of a therapeutically effectiveamount of a compound provided herein, including a single enantiomer, amixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, results in a 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 99% or more reduction in the viral titer relative toa subject without administration of the compound, as determined at 1day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days afterthe administration by a method known in the art.

In certain embodiments, administration of a therapeutically effectiveamount of a compound provided herein, including a single enantiomer, amixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, results in a 1, 2, 3, 4, 5, 10, 15, 20, 25,50, 75, 100 or more fold reduction in the viral titer relative to asubject without administration of the compound, as determined at 1 day,2 days, 3 days, 4 days, 5 days, 10 days, 15 days, or 30 days after theadministration by a method known in the art.

Further provided herein is a method for inhibiting the replication of anHCV virus, which comprises contacting the virus with a therapeuticallyeffective amount of a compound provided herein, including a singleenantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In certain embodiments, the contacting of the virus with atherapeutically effective amount of a compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, resultsin a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or morereduction in the virus titer relative to the virus without such contact,as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15days, or 30 days after the initial contact, by a method known in theart.

In certain embodiments, the contacting of the virus with atherapeutically effective amount of a compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, resultsin a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more reductionin the virus titer relative to the virus without such contact, asdetermined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days,or 30 days after the initial contact, by a method known in the art.

In certain embodiments, the contacting of the virus with atherapeutically effective amount of a compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, resultsin a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or morereduction in the viral titer relative to the virus without such contact,as determined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15days, or 30 days after the initial contact by a method known in the art.

In certain embodiments, the contacting of the virus with atherapeutically effective amount of a compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, resultsin a 1, 2, 3, 4, 5, 10, 15, 20, 25, 50, 75, 100 or more fold reductionin the viral titer relative to the virus without such contact, asdetermined at 1 day, 2 days, 3 days, 4 days, 5 days, 10 days, 15 days,or 30 days after the initial contact, by a method known in the art.

Also provided herein is a method for treating, preventing, orameliorating one or more symptoms of a liver disease or disorderassociated with an HCV infection, comprising administering to a subjecta therapeutically effective amount of the compound provided herein,including a single enantiomer, a mixture of an enantiomeric pair, anindividual diastereomer, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.Non-limiting examples of diseases associated with HCV infection includechronic hepatitis, cirrhosis, hepatocarcinoma, or extra hepaticmanifestation.

Provided herein is a method for inhibiting the activity of a polymerase,which comprises contacting the polymerase with an effective amount of acompound provided herein, including a single enantiomer, a mixture of anenantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof. In one embodiment, the polymerase is hepatitis CNS5B polymerase.

Depending on the condition, disorder, or disease, to be treated and thesubject's condition, a compound provided herein may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration, and may beformulated, alone or together, in suitable dosage unit withpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

The dose may be in the form of one, two, three, four, five, six, or moresub-doses that are administered at appropriate intervals per day. Thedose or sub-doses can be administered in the form of dosage unitscontaining from about 0.1 to about 1000 milligram, from about 0.1 toabout 500 milligrams, or from 0.5 about to about 100 milligram activeingredient(s) per dosage unit, and if the condition of the patientrequires, the dose can, by way of alternative, be administered as acontinuous infusion.

In certain embodiments, an appropriate dosage level is about 0.01 toabout 100 mg per kg patient body weight per day (mg/kg per day), about0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, orabout 0.05 to about 10 mg/kg per day, which may be administered insingle or multiple doses. A suitable dosage level may be about 0.01 toabout 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about0.1 to about 10 mg/kg per day. Within this range the dosage may be about0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, orabout 10 to about 50 mg/kg per day.

Combination Therapy

The compounds provided herein may also be combined or used incombination with other therapeutic agents useful in the treatment and/orprevention of an HCV infection.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent) to the subject.Triple therapy is also contemplated herein.

As used herein, the term “synergistic” includes a combination of acompound provided herein and another therapy (e.g., a prophylactic ortherapeutic agent) which has been or is currently being used to treat,prevent, or manage a disease or disorder, which is more effective thanthe additive effects of the therapies. A synergistic effect of acombination of therapies (e.g., a combination of prophylactic ortherapeutic agents) permits the use of lower dosages of one or more ofthe therapies and/or less frequent administration of said therapies to asubject with a disorder. The ability to utilize lower dosages of atherapy (e.g., a prophylactic or therapeutic agent) and/or to administersaid therapy less frequently reduces the toxicity associated with theadministration of said therapy to a subject without reducing theefficacy of said therapy in the prevention or treatment of a disorder).In addition, a synergistic effect can result in improved efficacy ofagents in the prevention or treatment of a disorder. Finally, asynergistic effect of a combination of therapies (e.g., a combination ofprophylactic or therapeutic agents) may avoid or reduce adverse orunwanted side effects associated with the use of either therapy alone.

The compound provided herein can be administered in combination oralternation with another therapeutic agent, such as an anti-HCV agent.In combination therapy, effective dosages of two or more agents areadministered together, whereas in alternation or sequential-steptherapy, an effective dosage of each agent is administered serially orsequentially. The dosages given will depend on absorption, inactivationand excretion rates of the drug as well as other factors known to thoseof skill in the art. It is to be noted that dosage values will also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimens andschedules should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the compositions.

It has been recognized that drug-resistant variants of HCV can emergeafter prolonged treatment with an antiviral agent. Drug resistance mosttypically occurs due to the mutation of a gene that encodes for anenzyme used in viral replication. The efficacy of a drug against theviral infection can be prolonged, augmented, or restored byadministering the compound in combination or alternation with a second,and perhaps third, antiviral compound that induces a different mutationfrom that caused by the principle drug. Alternatively, thepharmacokinetics, biodistribution or other parameters of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the virus.

In certain embodiments, the compound provided herein is combined withone or more agents selected from the group consisting of an interferon,ribavirin, amantadine, an interleukin, a NS3 protease inhibitor, acysteine protease inhibitor, a phenanthrenequinone, a thiazolidine, abenzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotideanalogue, a nucleoside analogue, a gliotoxin, a cerulenin, an antisensephosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependenttranslation, and a ribozyme.

In certain embodiments, the compound provided herein is combined with aHCV protease inhibitor, including, but not limited to, Medivir HCVprotease inhibitor (Medivir/Tobotec); ITMN-191 (InterMune), SCH 503034(Schering), VX950 (Vertex); substrate-based NS3 protease inhibitors asdisclosed in WO 98/22496; Attwood et al., Antiviral Chemistry andChemotherapy 1999, 10, 259-273; DE 19914474; WO 98/17679; WO 99/07734;non-substrate-based NS3 protease inhibitors, such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo et al., Biochem.Biophys. Res. Commun. 1997, 238, 643-647), RD3-4082, RD3-4078, SCH68631, and a phenanthrenequinone (Chu et al., Tetrahedron Letters 1996,37, 7229-7232); SCH 351633 (Chu et al., Bioorganic and MedicinalChemistry Letters 1999, 9, 1949-1952); Eglin c, a potent polymeraseinhibitor (Qasim et al., Biochemistry 1997, 36, 1598-1607).

Other suitable protease inhibitors for the treatment of HCV includethose disclosed in, for example, U.S. Pat. No. 6,004,933, whichdiscloses a class of cysteine protease inhibitors of HCV endopeptidase2.

Additional hepatitis C virus NS3 protease inhibitors include thosedisclosed in, for example, Llinàs-Brunet et al., Bioorg. Med. Chem.Lett. 1998, 8, 1713-1718; Steinkühler et al., Biochemistry 1998, 37,8899-8905; U.S. Pat. Nos. 5,538,865; 5,990,276; 6,143,715; 6,265,380;6,323,180; 6,329,379; 6,410,531; 6,420,380; 6,534,523; 6,642,204;6,653,295; 6,727,366; 6,838,475; 6,846,802; 6,867,185; 6,869,964;6,872,805; 6,878,722; 6,908,901; 6,911,428; 6,995,174; 7,012,066;7,041,698; 7,091,184; 7,169,760; 7,176,208; 7,208,600; U.S. Pat. App.Pub. Nos.: 2002/0016294, 2002/0016442; 2002/0037998; 2002/0032175;2004/0229777; 2005/0090450; 2005/0153877; 2005/176648; 2006/0046956;2007/0021330; 2007/0021351; 2007/0049536; 2007/0054842; 2007/0060510;2007/0060565; 2007/0072809; 2007/0078081; 2007/0078122; 2007/0093414;2007/0093430; 2007/0099825; 2007/0099929; 2007/0105781; WO 98/17679; WO98/22496; WO 99/07734; WO 00/059929; WO 00/09543; WO 02/060926; WO02/08187; WO 02/008251; WO 02/008256; WO 02/08198; WO 02/48116; WO02/48157; WO 02/48172; WO 03/053349; WO 03/064416; WO 03/064456; WO03/099274; WO 03/099316; WO 2004/032827; WO 2004/043339; WO 2005/037214;WO 2005/037860; WO 2006/000085; WO 2006/119061; WO 2006/122188; WO2007/001406; WO 2007/014925; WO 2007/014926; and WO 2007/056120.

Other protease inhibitors include thiazolidine derivatives, such asRD-1-6250, RD4 6205, and RD4 6193, which show relevant inhibition in areverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5Bsubstrate (Sudo et al., Antiviral Research 1996, 32, 9-18);thiazolidines and benzanilides identified in Kakiuchi et al., FEBS Lett.1998, 421, 217-220; Takeshita et al., Analytical Biochemistry 1997, 247,242-246.

Suitable helicase inhibitors include, but are not limited to, thosedisclosed in U.S. Pat. No. 5,633,358; and WO 97/36554.

Suitable nucleotide polymerase inhibitors include, but are not limitedto, gliotoxin (Ferrari et al., Journal of Virology 1999, 73, 1649-1654),and the natural product cerulenin (Lohmann et al., Virology 1998, 249,108-118).

Suitable interfering RNA (iRNA) based antivirals include, but are notlimited to, short interfering RNA (siRNA) based antivirals, such asSirna-034 and those described in WO/03/070750, WO 2005/012525, and U.S.Pat. Pub. No. 2004/0209831.

Suitable antisense phosphorothioate oligodeoxynucleotides (S-ODN)complementary to sequence stretches in the 5′ non-coding region (NCR) ofHCV virus include, but are not limited to those described in Alt et al.,Hepatology 1995, 22, 707-717, and nucleotides 326-348 comprising the 3′end of the NCR and nucleotides 371-388 located in the core coding regionof HCV RNA (Alt et al., Archives of Virology 1997, 142, 589-599;Galderisi et al., Journal of Cellular Physiology 1999, 181, 251-257);

Suitable inhibitors of IRES-dependent translation include, but are notlimited to, those described in Japanese Pat. Pub. Nos.: JP 08268890 andJP 10101591.

Suitable ribozymes include those disclosed in, for example, U.S. Pat.Nos. 6,043,077; 5,869,253 and 5,610,054.

Suitable nucleoside analogs include, but are not limited to, thecompounds described in U.S. Pat. Nos. 6,660,721; 6,777,395; 6,784,166;6,846,810; 6,927,291; 7,094,770; 7,105,499; 7,125,855; and 7,202,224;U.S. Pat. Pub. Nos. 2004/0121980; 2005/0009737; 2005/0038240; and2006/0040890; WO 99/43691; WO 01/32153; WO 01/60315; WO 01/79246; WO01/90121, WO 01/92282, WO 02/18404; WO 02/32920, WO 02/48165, WO02/057425; WO 02/057287; WO 2004/002422, WO 2004/002999, and WO2004/003000.

Other miscellaneous compounds that can be used as second agents include,for example, 1-amino-alkylcyclohexanes (U.S. Pat. No. 6,034,134), alkyllipids (U.S. Pat. No. 5,922,757), vitamin E and other antioxidants (U.S.Pat. No. 5,922,757), squalene, amantadine, bile acids (U.S. Pat. No.5,846,964), N-(phosphonacetyl)-L-aspartic acid (U.S. Pat. No.5,830,905), benzenedicarboxamides (U.S. Pat. No. 5,633,388),polyadenylic acid derivatives (U.S. Pat. No. 5,496,546),2′,3′-dideoxyinosine (U.S. Pat. No. 5,026,687), benzimidazoles (U.S.Pat. No. 5,891,874), plant extracts (U.S. Pat. Nos. 5,725,859;5,837,257; and 6,056,961), and piperidines (U.S. Pat. No. 5,830,905).

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus interferon, including, but not limited to, INTRON® A (interferonalfa-2b) and PEGASYS® (Peginterferon alfa-2a); ROFERON® A (recombinantinterferon alfa-2a), INFERGEN® (interferon alfacon-1), and PEG-INTRON®(pegylated interferon alfa-2b). In one embodiment, the anti-hepatitis Cvirus interferon is INFERGEN®, IL-29 (PEG-Interferon lambda), R7025(Maxy-alpha), BELEROFON®, oral interferon alpha, BLX-883 (LOCTERON®),omega interferon, MULTIFERON®, medusa interferon, ALBUFERON®, or REBIF®.

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus polymerase inhibitor, such as ribavirin, viramidine, NM 283(valopicitabine), PSI-6130, R1626, HCV-796, or R7128.

In certain embodiments, the one or more compounds provided herein areadministered in combination with ribavirin and an anti-hepatitis C virusinterferon, such as INTRON® A (interferon alfa-2b), PEGASYS®(Peginterferon alfa-2a), ROFERON® A (recombinant interferon alfa-2a),INFERGEN® (interferon alfacon-1), and PEG-INTRON® (pegylated interferonalfa-2b),

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus protease inhibitor, such as ITMN-191, SCH 503034, VX950(telaprevir), or Medivir HCV protease inhibitor.

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus vaccine, including, but not limited to, TG4040, PEVIPRO™,CGI-5005, HCV/MF59, GV1001, IC41, and INNO0101 (E1).

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus monoclonal antibody, such as AB68 or XTL-6865 (formerly HepX-C);or an anti-hepatitis C virus polyclonal antibody, such as cicavir.

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with an anti-hepatitis Cvirus immunomodulator, such as ZADAXIN® (thymalfasin), NOV-205, oroglufanide.

In certain embodiments, one or more compounds provided herein areadministered in combination or alternation with NEXAVAR®, doxorubicin,PI-88, amantadine, JBK-122, VGX-410C, MS-3253 (celgosivir), SUVUS®(BIVN-401 or virostat), PF-03491390 (formerly IDN-6556), G126270,UT-231B, DEBIO-025, EMZ702, ACH-0137171, MitoQ, ANA975, AVI-4065,bavituximab (tarvacin), ALINIA® (nitrazoxanide) or PYN17.

In certain embodiments, the compounds provided herein can be combinedwith one or more steroidal drugs known in the art, including, but notlimited to the group including, aldosterone, beclometasone,betamethasone, deoxycorticosterone acetate, fludrocortisone,hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone,dexamethasone, and triamcinolone.

In certain embodiments, the compounds provided herein can be combinedwith one or more antibacterial agents known in the art, including, butnot limited to the group including amikacin, amoxicillin, ampicillin,arsphenamine, azithromycin, aztreonam, azlocillin, bacitracin,carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin,cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime,cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin,clarithromycin, clindamycin, cloxacillin, colistin, dalfopristin,demeclocycline, dicloxacillin, dirithromycin, doxycycline, erythromycin,enrofloxacin, ertepenem, ethambutol, flucloxacillin, fosfomycin,furazolidone, gatifloxacin, geldanamycin, gentamicin, herbimycin,imipenem, isoniazid, kanamycin, levofloxacin, linezolid, lomefloxacin,loracarbef, mafenide, moxifloxacin, meropenem, metronidazole,mezlocillin, minocycline, mupirocin, nafcillin, neomycin, netilmicin,nitrofurantoin, norfloxacin, ofloxacin, oxytetracycline, penicillin,piperacillin, platensimycin, polymyxin B, prontocil, pyrazinamide,quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin,sulfacetamide, sulfamethizole, sulfamethoxazole, teicoplanin,telithromycin, tetracycline, ticarcillin, tobramycin, trimethoprim,troleandomycin, trovafloxacin, and vancomycin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antifungal agents known in the art, including, but notlimited to the group including amorolfine, amphotericin B,anidulafungin, bifonazole, butenafine, butoconazole, caspofungin,ciclopirox, clotrimazole, econazole, fenticonazole, filipin,fluconazole, isoconazole, itraconazole, ketoconazole, micafungin,miconazole, naftifine, natamycin, nystatin, oxyconazole, ravuconazole,posaconazole, rimocidin, sertaconazole, sulconazole, terbinafine,terconazole, tioconazole, and voriconazole.

In certain embodiments, the compounds provided herein can be combinedwith one or more anticoagulants known in the art, including, but notlimited to the group including acenocoumarol, argatroban, bivalirudin,lepirudin, fondaparinux, heparin, phenindione, warfarin, andximelagatran.

In certain embodiments, the compounds provided herein can be combinedwith one or more thrombolytics known in the art, including, but notlimited to the group including anistreplase, reteplase, t-PA (alteplaseactivase), streptokinase, tenecteplase, and urokinase.

In certain embodiments, the compounds provided herein can be combinedwith one or more non-steroidal anti-inflammatory agents known in theart, including, but not limited to, aceclofenac, acemetacin, amoxiprin,aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib,choline magnesium salicylate, diclofenac, diflunisal, etodolac,etoricoxib, faislamine, fenbufen, fenoprofen, flurbiprofen, ibuprofen,indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib,meclofenamic acid, mefenamic acid, meloxicam, metamizole, methylsalicylate, magnesium salicylate, nabumetone, naproxen, nimesulide,oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicylsalicylate, sulindac, sulfinpyrazone, suprofen, tenoxicam, tiaprofenicacid, and tolmetin.

In certain embodiments, the compounds provided herein can be combinedwith one or more antiplatelet agents known in the art, including, butnot limited to, abeiximab, cilostazol, clopidogrel, dipyridamole,ticlopidine, and tirofibin.

The compounds provided herein can also be administered in combinationwith other classes of compounds, including, but not limited to,endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon;thromboxane receptor antagonists, such as ifetroban; potassium channelopeners; thrombin inhibitors, such as hirudin; growth factor inhibitors,such as modulators of PDGF activity; platelet activating factor (PAF)antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,abeiximab, eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g.,clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, suchas warfarin; low molecular weight heparins, such as enoxaparin; FactorVIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutralendopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACEinhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductaseinhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522(also known as rosuvastatin, atavastatin, or visastatin); squalenesynthetase inhibitors; fibrates; bile acid sequestrants, such asquestran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors;MTP Inhibitors; calcium channel blockers, such as amlodipine besylate;potassium channel activators; alpha-adrenergic agents; beta-adrenergicagents, such as carvedilol and metoprolol; antiarrhythmic agents;diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid,ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide,triamterene, amiloride, and spironolactone; thrombolytic agents, such astissue plasminogen activator (tPA), recombinant tPA, streptokinase,urokinase, prourokinase, and anisoylated plasminogen streptokinaseactivator complex (APSAC); anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrimidine analogues; antibiotics, such asanthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin;enzymes, such as L-asparaginase; farnesyl-protein transferaseinhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathioprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxiband rofecoxib; and miscellaneous agents such as, hydroxyurea,procarbazine, mitotane, hexamethylmelamine, gold compounds, platinumcoordination complexes, such as cisplatin, satraplatin, and carboplatin.

In certain embodiments, the pharmaceutical compositions provided hereinfurther comprise a second antiviral agent as described herein. In oneembodiment, the second antiviral is selected from the group consistingof an interferon, ribavirin, an interleukin, an NS3 protease inhibitor,a cysteine protease inhibitor, a phenanthrenequinone, a thiazolidine, abenzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotideanalogue, a nucleoside analogue, a gliotoxin, a cerulenin, an antisensephosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependenttranslation, and a ribozyme. In another embodiment, the second antiviralagent is an interferon. In yet another embodiment, the t interferon isselected from the group consisting of pegylated interferon alpha 2a,interferon alphcon-1, natural interferon, ALBUFERON®, interferonbeta-1a, omega interferon, interferon alpha, interferon gamma,interferon tau, interferon delta, and interferon gamma-1b.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of a compoundprovided herein, including a single enantiomer, a mixture of anenantiomeric pair, an individual diastereomer, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer, amixture of an enantiomeric pair, an individual diastereomer, or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr (hours); min (minutes);TLC (thin layer chromatography); HPLC (high performance liquidchromatography); SCX (strong cation exchange); MS (mass spectrometry);ESI (electrospray ionization); R_(t) (retention time); SiO₂ (silica);THF (tetrahydrofuran); CD₃OD (deuterated methanol); CDCl₃ (deuteratedchloroform); DCE (dichloroethane); DCM (dichloromethane); DMF(dimethyformamide); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate);CHCl₃ (chloroform); DMF (N,N-dimethylformamide); DMA(N,N-dimethyacetamide); MeOH (methanol); EtOH (ethanol); HCl(hydrochloric acid); LiOH (lithium hydroxide); NaOH (sodium hydroxide);KOH (potassium hydroxide); Cs₂CO₃ (cesium carbonate); DIPEA(N,N-diisopropylethylamine); TEA (trietlylamine); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene; CDI (carbonyldiimidazole); TBTU(O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate);Ac (acetyl); Me (methyl); Et (ethyl); tBu (tert-butyl); Boc(tert-butoxylcarbony); Bn (benzyl); and Ts (tosylate).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated in Schemes 4 to 6are intended to exemplify the applicable chemistry through the use ofspecific examples and are not indicative of the scope of the disclosure.

Intermediate 24 (2-amino-5-nitro-phenyl)-phosphonic acid diethyl ester

2-iodo-4-nitro aniline (7.57 mmol), triethyl phosphite (15.1 mmol) andpalladium acetate (1.51 mmol) were mixed together in acetonitrile (36ml), in a microwave tube. The vessel was sealed and placed in amicrowave to react at 160° C., for 30 min. After cooling to roomtemperature, acetonitrile was removed. The residue obtained was dilutedin ethyl acetate, washed with hydrochloric solution (1N) and phosphatebuffer solution (pH 7). The solvent was removed and the crude materialwas purified by silica gel chromatography to yield intermediate 24,which was a brown solid. Intermediate 24 was characterized by thefollowing spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.21 (t,J=7.1 Hz, 6H), 3.92 (m, 4H), 5.13 (s, NH₂), 6.50 (t, J=7.8 Hz, 1H), 6.61(m, 2H); ³¹P NMR (DMSO-d₆, 162 MHz) δ (ppm) 21.68 (s, 1P); and MS (ESI,EI⁺) m/z=275 (MH⁺).

Intermediate 25 (2,5-diaminophenyl)-phosphonic acid diethyl ester

Intermediate 24 (3.65 mmol) was dissolved in methanol (5 ml) Pd/C wasadded under nitrogen. After several cycles vacuum/nitrogen, hydrogen wasintroduced at atmospheric pressure. The reaction mixture was stirred atroom temperature, under hydrogen, overnight. The reaction mixture wasthen filtered through celite and concentrated to yield intermediate 25,which was a brown solid. Intermediate 25 was characterized by thefollowing spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.20 (t,J=7.05 Hz, 6H), 3.87-4.00 (m, 4H), 4.45 (s, NH₂), 5.15 (s, NH₂), 6.50(t, J=8 Hz, 1H), 6.58-6.60 (m, 2H); ¹P NMR (DMSO-d₆, 162 MHz) δ (ppm)21.46 (s, 1P); and MS (ESI, EI⁺) m/z=245 (MH⁺).

Intermediate 26 (2-amino-5-methanesulfonaminylphenyl)-phosphonic aciddiethyl ester

To a stirred solution of the intermediate 25 (3.52 mmol), triethylamine(4.22 mmol) in dichloromethane (7 ml) at 0° C. was added methanesulfonyl chloride (4.22 mmol) under nitrogen. The reaction mixture wasstirred at room temperature, over night. The mixture was then quenchedwith phosphate buffer solution (pH 7). The organic layer was separated,concentrated and the crude material was purified by silica gelchromatography (dichloromethane/methanol) to yield intermediate 26,which was a beige solid. Intermediate 26 was characterized by thefollowing spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) δ (ppm) 1.34 (t,J=7.07 Hz, 6H), 2.94 (s, 3H), 4.04-4.22 (m, 4H), 5.14 (s, NH₂), 6.57 (s,NH), 6.66 (t, J=7.26, 1H), 7.29 (d, J=8.79 Hz, 1H), 7.39 (d, J=14.9 Hz,1H); ³¹P NMR (DMSO-d₆, 162 MHz) δ (ppm) 19.44 (s, 1P); and MS (ESI, EI⁺)m/z=323 (MH⁺).

Intermediate 108 N-tert-butyl-N′-(3,3-dimethyl-butylidene)-hydrazine

To the tert-butylhydrazine hydrochloride (24 mmol, Fluka) were addeddiethyl ether (35 ml) and triethylamine (24 mmol). After 5 minutes ofstirring, 3,3-dimethylbutyraldehyde (24 mmol) and anhydrous magnesiumsulfate (26.4 mmol) were added and this mixture was stirred at roomtemperature for 2 days. The salt was filtered on a pad of celite andrinced with ethyl acetate and the solvent was evaporated to giveintermediate 108, which was a yellow pale oil. Intermediate 108 wascharacterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400MHz) (ppm) 0.96 (s, 9H), 1.01 (s, 3H), 1.20 (s, 3H), 1.21 (s, 9H), 1.94(d, J=5.24 Hz, 0.67H), 2.1 (d, J=6.10 Hz, 2H), 6.63 (t, J=5.24 Hz,0.33H), 7.24 (t, J=6.10 Hz, 1H) (mixture of isomers).

Intermediate 109N-tert-butyl-N′-(3,3-dimethyl-butylidene)-hydrazinecarboxylic acid ethylester

The intermediate 108 (24 mmol) was dissolved in ethyl acetate (36 ml)(previously dried over MgSO₄) and the pyridine (33.6 mmol) was added.Then, the mixture was cooled down to 0° C. and ethyl chloroformate (33.6mmol) was added. This mixture was stirred at 30° C. overnight. Then, thesalts were filtered on autocup, rinced with ethyl acetate and thesolvent was evaporated to give an orange oil. This oil was purified bychromatography to give intermediate 109. Intermediate 109 wascharacterized by the following spectroscopic data: ¹H NMR (CDCl₃, 400MHz) (ppm) 1.03 (s, 9H), 1.24 (t, J=7.12 Hz, 3H), 1.39 (s, 9H), 2.27 (d,J=6.33 Hz, 2H), 4.12 (q, J=7.12 Hz, 2H), 7.74 (t, J=6.33 Hz, 1H).

Intermediate 110N-tert-butyl-N′-(3,3-dimethyl-butyl)-hydrazinecarboxylic acid ethylester

To a solution of intermediate 109 (24 mmol) in tetrahydrofurane (70 ml)were added under nitrogen the sodium cyanoborohydride (60 mmol) andthen, acid acetic (120 mmol). This reaction mixture was stirred at roomtemperature for 40 hours. The reaction was diluted with ethyl acetateand extracted with a saturated solution of NaHCO₃. The aqueous layerswere washed with ethyl acetate and the gathered organic layers weredried and concentrated under vacuo to give an oil. This oil wasdissolved in methanol (40 ml) and a solution 1N of sodium hydroxide(40.8 mmol) was added at room temperature. This mixture was stirred atroom temperature for 4 hours. Then, the methanol was removed byevaporation under vacuo, ethyl acetate was added and this mixture waswashed. After concentration, the residue was purified by chromatographyto give intermediate 110. Intermediate 110 was characterized by thefollowing spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.91 (s,9H), 1.26-1.31 (m, 1H), 1.29 (t, J=7.14 Hz, 3H), 1.37 (s, 9H), 1.42-1.46(m, 1H), 2.77 (brs, 2H), 3.8 (brs, 1H), 4.16 (q, J=7.14 Hz, 2H).

Intermediate 111N-tert-butyl-N′-(2-cyano-acetyl)-N′-(3,3-dimethyl-butyl)-hydrazinecarboxylicacid ethyl ester

A solution of intermediate 110 (4.1 mmol) and cyanoacetic acid (4.1mmol) in anhydrous dimethylformamide (18 ml) was treated withdicyclohexylcarbodiimide (4.1 mmol). After stirring at room temperatureovernight, the reaction mixture was filtered over celite and thefiltrate was poured into water and an extraction was realized with ethylacetate. After the aqueous layers were extracted with ethyl acetate, thecombined organic layers were dried and concentrated under vacuo. Theresidue was purified by chromatography to give intermediate 111, whichwas an Oil. Intermediate 111 was characterized by the followingspectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.93 (s, 9H), 1.3 (t,J=7.12 Hz, 3H), 1.47 (s, 9H), 1.54-1.64 (m, 2H), 3.26-3.34 (m, 1H), 3.5(s, 2H), 3.70-3.78 (m, 1H), 4.21 (q, J=7.12 Hz, 2H).

Intermediate 1121-tert-butyl-2-(3,3-dimethyl-butyl)-5-hydroxy-3-oxo-2,3-dihydropyrrole-4-carbonitrile

A solution of intermediate 111 (0.739 mmol) in anhydrous tert butanol(24 ml) was treated with potassium tert-butoxide (1.85 mmol). Afterstirring 5 minutes at 140° C. and 5 minutes at 150° C., the reactionmixture was quenched with HCl 2N, extracted with ethyl acetate, driedover sodium sulfate and concentrated in vacuo to give intermediate 112,which was a yellow oil. Intermediate 112 was characterized by thefollowing spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.91-0.93(m, 9H), 1.37-1.42 (m, 1H), 1.47-1.50 (m, 9H), 1.56-1.63 (m, 1H),3.70-3.77 (m, 2H), 6.98 (brs, 1H).

Example 681-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-ethoxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 68 was synthesized from intermediate 112 and intermediate 26. Toa solution of intermediate 112 (0.31 mmol) in dioxane (3 ml) was addedintermediate 26 (0.465 mmol). This mixture was treated dropwise withtrimethyl aluminium (1.55 mmol) and stirred at 80° C. for 4 hours. Then,the reaction mixture was quenched with HCl 1N, diluted with TBDME orethyl acetate, washed with water and brine, dried over sodium sulfateand concentrated in vacuo after purification with preparative HPLC togive example 68, which was a white solid. Example 68 was characterizedby the following spectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) (ppm)0.92-0.93 (m, 9H), 1.34-1.38 (m, 3H), 1.47-1.48 (m, 9H), 3.05 (s, 3H),3.58-3.65 (m, 1H), 3.71-3.79 (m, 2H), 4.16-4.24 (m, 2H), 7.19-7.23 (m,1H), 7.64-7.68 (m, 2H), 11.2 (brs, 0.5H), 11.5 (brs, 0.5H); ³¹P NMR(CDCl₃, 400 MHz) (ppm) 0.42 (s, 1P); and MS (ESI, EI⁺) m/z=542 (MH⁺).Example 68 is equivalent to Compound V-1.

Example 691-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-hydroxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 69 was synthesized from example 68. Example 68 (0.05 mmol) wasdissolved in 1,2-dichloroethane (2.5 ml) under nitrogen andtetramethylsilylbromide (0.5 mmol). The mixture was stirred at 60° C.for 2 hours and then concentrated to dryness. The residue was quenchedwith methanol before new concentration under vacuo. The residue waspurified by chromatography (RP18) and lyophilisation to give example 69,which was a white powder. Example 69 was characterized by the followingspectroscopic data: ¹H NMR (DMSO-d₆, 400 MHz) (ppm) 0.85 (s, 9H),1.26-1.30 (m, 2H), 1.36 (s, 9H), 3 (s, 3H), 3.46-3.51 (m, 2H), 7.39-7.49(m, 3H), 9.99 (brs, 1H), 10.86 (brs, 0.5H), 11.03 (brs, 0.5H); ³¹P NMR(DMSO-d₆, 400 MHz) (ppm) −13.74 (s, 1P); and MS (ESI, EI⁺) m/z=513.89(MH⁺). Example 69 is equivalent to Compound V-2.

Example 702-(3,3-dimethyl-butyl)-4-(1-hydroxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 70 was a by-product of the reaction realized to obtain example69, which was a white solid. Example 70 was characterized by thefollowing spectroscopic data: 1H NMR (DMSO-d₆, 400 MHz) (ppm) 0.89 (s,9H), 1.39-1.43 (m, 2H), 2.93 (s, 3H), 3.33-3.39 (m, 2H), 7.11 (dd,J=5.89 Hz and J=8.58 Hz, 1H), 7.24 (dd, J=2.33 Hz and J=8.63 Hz, 1H),7.33 (dd, J=1.90 Hz and J=13.49 Hz, 1H), 9.07 (brs, 1H), 9.36 (brs, 1H),10.61 (s, 1H); ³¹P NMR (DMSO-d₆, 400 MHz) (ppm) −13.80 (s, 1P); and MS(ESI, EI⁺) m/z=457.88 (MH⁺). Example 70 is equivalent to Compound V-3.

Example 711-tert-butyl-2-(3,3-dimethyl-butyl)-4-(1-methoxy-1-oxo-1,4-dihydro-7-methanesulfonamyl-1-benzo[1,2,4]phosphadiazin-3-yl)-5-hydroxy-2,3-dihydropyrazol-2-one

Example 71 was synthesized from example 69. To a stirred solution ofexample 69 (0.042 mmol) in dichloromethane (2 ml) and a few drops ofdimethylformamide, oxalyl chloride (0.0063 mmol) was added dropwise,under nitrogen. The reaction mixture was stirred at room temperature,under nitrogen for 24 hours. Methanol was then added and the mixture wasstirred for one hour. Solvents were concentrated under reduced pressureand the crude material was purified using preparative HPLC to yieldexample 71, which was a white solid. Example 71 was characterized by thefollowing spectroscopic data: ¹H NMR (CDCl₃, 400 MHz) (ppm) 0.92-0.93(m, 9H), 1.33-1.44 (m, 2H), 1.47-1.48 (m, 9H), 3.06 (s, 3H), 3.58-3.66(m, 1H), 3.69-3.77 (m, 1H), 3.82 (d, J=12.36 Hz, 3H), 7.18-7.24 (m, 1H),7.65-7.70 (m, 2H), 8.04 (brs, 1H), 11.22 (brs, 0.5H), 11.55 (brs, 0.5H);³¹P NMR (CDCl₃, 400 MHz) (ppm) 2.25 (s, 1P); and MS (ESI, EI⁺)m/z=527.92 (MH⁺). Example 71 is equivalent to Compound V-4.

Example 72 HCV Polymerase Assay

The HCV polymerase assay was performed in 96-well streptavidin-coatedmicrotiter plates (Pierce) using 50 nM HCV genotype 1b polymerase(strain J4) from Replizyme, 15 μM bromo-UTP, 1 μg/ml 5′-biotynilatedoligo (rU12), 1 μg/ml poly(rA) in 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 0.5μg/ml BSA, 1 mM DTT, 0.02 U/μl RNasin, 5% DMSO and 25 mM KCL. The 60-μlreaction was incubated at 35° for 60 min and terminated by adding 20 μL0.5 M EDTA pH 8.0. The BrUTP incorporated onto the biotinylated primerwas quantified by ELISA using a peroxidase-labeled anti-BrdU monoclonalantibody (Roche) and TMB (Sigma) substrate and the plates were read at630 nm with the Tecan Sunrise Stectrophotometer. The compounds wereroutinely solubilised at a concentration of 15 mM in DMSO and tested ata variety of concentrations in assay buffer containing a final DMSOconcentration of 5%. The IC₅₀ values were determined from the percentinhibition versus concentration data using a sigmoidal non-linearregression analysis based on four parameters with Tecan Magellansoftware.

The biological results are summarized in Table 1 (IC₅₀), wherein Arepresents a value smaller than 100 nM, B represents a value between 100nM to 10 μM, and C represents a value greater than 10 μM.

Example 73 HCV Replicon Assay

General procedure: Huh-7 cells containing HCV Con1 subgenomic replicon(GS4.1 cells) were grown in Dulbecco's Modified Eagle Medium (DMEM)supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 110mg/L sodium pyruvate, 1× non-essential amino acids, 100 U/mLpenicillin-streptomycin, and 0.5 mg/mL G418 (Invitrogen). Fordose-response testing, the cells were seeded in 96-well plates at7.5×10³ cells/well in a volume of 50 μL, and incubated at 37° C./5% CO₂.Three hours after plating, 50 μL of ten 2-fold serial dilutions ofcompounds (highest concentration, 75 μM) were added, and cell cultureswere incubated at 37° C./5% CO₂ in the presence of 0.5% DMSO.Alternatively, compounds were tested at a single concentration of 15 μM.In all cases, Huh-7 cells lacking the HCV replicon served as negativecontrol. The cells were incubated in the presence of compounds for 72 hrafter which they were monitored for expression of the NS4A protein byenzyme-linked immunosorbent assay (ELISA). For this, the plates werethen fixed for 1 min with acetone/methanol (1:1, v/v), washed twice withphosphate-buffered saline (PBS), 0.1% Tween 20, blocked for 1 hr at roomtemperature with TNE buffer containing 10% FBS and then incubated for 2hr at 37° C. with the anti-NS4A mouse monoclonal antibody A-236(ViroGen) diluted in the same buffer. After washing three times withPBS, 0.1% Tween 20, the cells were incubated 1 hr at 37° C. withanti-mouse immunoglobulin G-peroxidase conjugate in TNE, 10% FBS. Afterwashing as described above, the reaction was developed withO-phenylenediamine (Zymed). The reaction was stopped after 30 min with 2N H₂SO₄, and absorbance was read at 492 nm using Sunrise Tecanspectrophotometer. EC₅₀ values were determined from the % inhibitionversus concentration data using a sigmoidal non-linear regressionanalysis based on four parameters with Tecan Magellan software. Whenscreening at a single concentration, the results were expressed as %inhibition at 15 μM.

The biological results are summarized in Table 1 (EC₅₀ and CC₅₀),wherein A represents a value smaller than 100 nM, B represents a valuebetween 100 nM to 10 μM, and C represents a value greater than 10 μM.

TABLE 1 IC50 EC50 CC50 Compound (μM) (μM) (μM)

(V-2) A B C

(V-3) B C C

(V-4) A B C

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

1. A compound of Formula V′:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, wherein: R¹ is H, alkyl, arylalkyl, heteroarylalkyl,—NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl,arylalkyl, alkenyl, alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl;R⁴ is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl; R^(4′) is H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkylor heteroaryl; R⁵ is H, halogen, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R⁴ and R⁵ togetherform a part of a 3-8 membered heterocycloalkyl ring; R^(5′) is H,halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, heteroaryl, —NR⁸R¹⁰, alkenyl, or alkynl; R^(6′)is H, halogen, cyano, nitro, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,—C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl, or R^(5′) and R^(6′)together form a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring; R¹² is F, —OR⁸, —SR⁸, —NR⁸R⁹,alkyl, or aryl; each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl,heterocyclyl, C₁₋₆ alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl;each R⁹ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸and R⁹ together with the N atom to which they are attached formheterocyclyl; each R¹⁰ is independently H, alkyl, aryl, sulfonyl,C(O)R⁸, C(O)OR⁸ or C(O)NR⁸R⁹; Y is O or S; and wherein each alkyl, aryl,arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,sulfonyl, or alkyl-cycloalkyl is optionally substituted.
 2. The compoundof claim 1, wherein each pair of R^(5′) and R^(6′) togetherindependently forms a part of a 3-8 membered cycloalkyl, aryl,heterocycloalkyl or heteroaryl ring.
 3. The compound of claim 1, whereinthe compound of Formula V′ has the following formula I^(″) or II″:

wherein each A is independently CR¹⁸ or N; each A′ is independentlyCR¹⁵R¹⁶, NR¹⁷, N, CR¹⁵, N-oxide, N—OR⁸—, S or O; each of R¹⁵ isindependently a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl; R¹⁶ is a bond, H, halogen,—NR¹⁰SO₂R⁸, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆alkyl)-NR^(9′)S(O)₂NR⁸R¹⁰, —(C₁-C₆ alkyl)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹,—C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, or heteroaryl; R¹⁷ is abond, H, alkyl, aryl-CH₂—, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸,sulfonyl, aryl, arylalkyl, alkenyl, alkynyl, heterocyclylalkyl orheteroaryl; R¹⁸ is a bond, H, halogen, —NR¹⁰SO₂R⁸, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R¹⁰,—(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹,—C(O)OR⁸, alkyl, aryl, or heteroaryl; each R¹⁴ is independently H,halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, cyano,nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹,—C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl), —O—(C₁-C₆ alkoxy), —O—(C₁-C₆alkylene)-cyano, —O—(C₁-C₆ alkylene)-C(O)R^(9′), —OCHR^(9′)C(O)O—R⁸,—OCHR^(9′)C(O)NHOH, —O—(C₁-C₆ alkyl)-C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸, —O—(C₁-C₆alkylene)-NR^(9′)C(O)NR⁸R⁹, —OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^(9′), —O—(C₁-C₆ alkyl)-S(O)₂R^(9′), —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆ alkylene)-S(O)₂R^(9′)—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆ alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹; n is independently an integerfrom 1 to 4; m is independently an integer from 1 to 3; R¹² is —OR⁸,—SR⁸, —NR⁸R⁹, alkyl, or aryl; and Z has the following structure:


4. A compound of Formula V:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof; R¹ is alkyl, arylalkyl, heteroarylalkyl, H, —NR¹⁰SO₂R⁸, —OR⁸,—NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, aryl, arylalkyl, alkenyl,alkynyl, heterocyclylalkyl, sulfonyl, or heteroaryl; R⁶ is H, halogen,—NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸, —C(O)NR⁸R⁹, —C(O)OR⁸, alkyl, aryl, orheteroaryl; R¹² is —OR⁸, —SR⁸, —NR⁸R⁹, alkyl, or aryl; each R¹⁴ isindependently H, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl,heteroaryl, cyano, nitro, OH, —NR¹⁰SO₂R⁸, —OR⁸, —NR⁸R⁹, —C(O)R⁸,C(O)NR⁸R⁹, —OCH₂C(O)NR⁸R⁹, —C(O)OR⁸, —O—(C₁-C₆ hydroxyalkyl), —O—(C₁-C₆alkoxy), —O—(C₁-C₆ alkylene)-cyano, —O—(C₁-C₆ alkylene)-C(O)R^(9′),—OCHR^(9′)C(O)O—R⁸, —OCHR^(9′)C(O)NHOH, —O—(C₁-C₆ alkyl)-C(O)NR⁸R⁹,—O—(C₁-C₆ alkylene)-NR^(9′)C(O)R⁸, —O—(C₁-C₆ alkylene)-NR^(9′)C(O)OR⁸,—O—(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹, —OCHR^(9′)C(O)NR⁸R⁹, —O—(C₁-C₆alkylene)-S(O)R^(9′), —O—(C₁-C₆ alkyl)-S(O)₂R^(9′), —O—(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —O—(C₁-C₆ alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —O—(C₁-C₆alkylene)-NR^(9′)S(O)₂R⁸—O—(C₁-C₆ alkylene)-S(O)₂R^(9′)—O—(C₁-C₆alkylene)-NR⁸R⁹, —(C₁-C₆ alkylene)-S(O)₂R⁸, —(C₁-C₆alkylene)-S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-S(O)R⁸, —(C₁-C₆alkylene)-C(O)R⁸, —(C₁-C₆ alkylene)-C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^(9′)C(O)R⁸, —(C₁-C₆ alkylene)-NR^(9′)S(O)₂R⁸, —(C₁-C₆alkylene)-NR^(9′)C(O)OR⁸, —(C₁-C₆ alkylene)-NR^(9′)C(O)NR⁸R⁹, —(C₁-C₆alkylene)-NR^(9′)S(O)₂NR⁸R⁹, —(C₁-C₆ alkylene)-C(O)OR⁸, —(C₁-C₆alkylene)-NR⁸R⁹, —NR⁸C(O)R⁹, —NR^(9′)S(O)₂NR⁸R⁹, —NR^(9′)S(O)₂NR⁸R¹⁰,—S(O)R^(9′), —S(O)₂R^(9′), or —S(O)₂NR⁸R⁹; n is an integer from 1 to 4;each R⁸ is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, heterocyclyl, C₁₋₆alkyl-C₃₋₇ cycloalkylene, or C₁₋₁₀ alkyl-siloxyl; each R⁹ isindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; or R⁸ and R⁹together with the N atom to which they are attached form heterocyclyl;each R^(9′) is independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, heteroaryl, or heterocyclyl; andeach R¹⁰ is independently H, alkyl, aryl, sulfonyl, C(O)R⁸, C(O)OR⁸ orC(O)NR⁸R⁹, wherein each alkyl, aryl, arylalkyl, heteroaryl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, sulfonyl, or alkyl-cycloalkyl isoptionally substituted.
 5. The compound of claim 4 according to FormulaVa:

or a single enantiomer, a mixture of an enantiomeric pair, an individualdiastereomer, a mixture of diastereomers, or any tautomeric formthereof, or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 6. The compound of claim 4, wherein the compound has thestructure of Formula Va.
 7. The compound of claim 4, wherein each alkyl,aryl, arylalkyl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,or alkyl-cycloalkyl is unsubstituted.
 8. The compound of claim 4,wherein R¹ is C₁₋₆ alkyl.
 9. The compound of claim 8, wherein R¹ is3,3-dimethylbutyl.
 10. The compound of claim 4, wherein R⁶ is hydrogenor halogen.
 11. The compound of claim 4, wherein R⁶ is tert-butyl. 12.The compound of claim 4, wherein R¹² is C₁₋₆ alkoxy.
 13. The compound ofclaim 12, wherein R¹² is methoxy.
 14. The compound of claim 12, whereinR¹² is ethoxy.
 15. The compound of claim 4, wherein R¹² is NH₂.
 16. Thecompound of claim 4, wherein R¹² is OH.
 17. The compound of claim 4,wherein R¹⁴ is hydrogen.
 18. The compound of claim 4, wherein R¹⁴ is—NHSO₂R⁸.
 19. The compound of claim 18, wherein R⁸ is C₁₋₆ alkyl. 20.The compound of claim 19, wherein R⁸ is methyl.
 21. The compound ofclaim 4, wherein R¹ is 3,3-dimethylbutyl; R⁶ is tert-butyl; R¹² ismethoxy, ethoxy, fluoro, NH₂ or OH; and R¹⁴ is hydrogen or —NHSO₂Me. 22.The compound of claim 4 according to the following formula:


23. The compound of claim 4 according to the following formula:


24. The compound of claim 4 according to the following formula:


25. A pharmaceutical composition comprising the compound of claim 1 andone or more pharmaceutically acceptable carriers.
 26. The pharmaceuticalcomposition of claim 25, further comprising a second antiviral agent.27. The pharmaceutical composition of claim 26, wherein the secondantiviral agent is selected from the group consisting of an interferon,ribavirin, an interleukin, an NS3 protease inhibitor, a cysteineprotease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide,a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, anucleoside analogue, a liotoxin, acerulenin, an antisensephosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependenttranslation, and a ribozyme.
 28. The pharmaceutical composition of claim27, wherein the second antiviral agent is an interferon.
 29. Thepharmaceutical composition of claim 28, wherein the interferon isselected from the group consisting of pegylated interferon alpha 2a,interferon alphcon-1, natural interferon, albuferon, interferon beta-1a,omega interferon, interferon alpha, interferon gamma, interferon tau,interferon delta, and interferon gamma-1b.
 30. The pharmaceuticalcomposition of claim 25, wherein the composition is formulated forsingle dose administration.
 31. The pharmaceutical composition of claim25, wherein the composition is formulated as an oral, parenteral, orintravenous dosage form.
 32. The pharmaceutical composition of claim 31wherein the oral dosage form is a tablet or capsule.
 33. Thepharmaceutical composition of claim 25, wherein the compound isadministered in a dose of about 0.5 milligram to about 1,000 milligramdaily.
 34. A method for treating or preventing an HCV infection, whichcomprises administering the compound of claim
 1. 35. A method fortreating or preventing an HCV infection, which comprises administeringthe pharmaceutical composition of claim
 25. 36. A method of treating,preventing, or ameliorating one or more symptoms of a liver disease ordisorder associated with an HCV infection, comprising administering thecompound of claim
 1. 37. A method of treating, preventing, orameliorating one or more symptoms of a liver disease or disorderassociated with an HCV infection, comprising administering thepharmaceutical composition of claim
 25. 38. The method of claim 34,wherein the method comprises administering a second antiviral agent, incombination or alternation.
 39. The method of claim 35, wherein themethod comprises administering a second antiviral agent, in combinationor alternation.
 40. The method of claim 38, wherein the second antiviralagent is selected from the group consisting of an interferon, ribavirin,amantadine, an interleukin, a NS3 protease inhibitor, a cysteineprotease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide,a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, anucleoside analogue, a liotoxin, acerulenin, an antisensephosphorothioate ologodeoxynucleotide, an inhibitor of IRES-dependenttranslation, and a ribozyme.
 41. The method of claim 39, wherein thesecond antiviral agent is selected from the group consisting of aninterferon, ribavirin, amantadine, an interleukin, a NS3 proteaseinhibitor, a cysteine protease inhibitor, a phenathrenequinone, athiazolidine, a benzanilide, a helicase inhibitor, a polymeraseinhibitor, a nucleotide analogue, a nucleoside analogue, a liotoxin,acerulenin, an antisense phosphorothioate ologodeoxynucleotide, aninhibitor of IRES-dependent translation, and a ribozyme.
 42. The methodof claim 38, wherein the second antiviral agent is an interferon. 43.The method of claim 39, wherein the second antiviral agent is aninterferon.
 44. The method of claim 42, wherein the interferon isselected from the group consisting of pegylated interferon alpha 2a,interferon alphcon-1, natural interferon, albuferon, interferon beta-1a,omega interferon, interferon alpha, interferon gamma, interferon tau,interferon delta, and interferon gamma-1b.
 45. The method of claim 43,wherein the interferon is selected from the group consisting ofpegylated interferon alpha 2a, interferon alphcon-1, natural interferon,albuferon, interferon beta-1a, omega interferon, interferon alpha,interferon gamma, interferon tau, interferon delta, and interferongamma-1b.
 46. A method for inhibiting replication of a virus in a host,which comprises contacting the host with the compound of claim
 1. 47. Amethod for inhibiting replication of a virus in a host, which comprisescontacting the host with the pharmaceutical composition of claim
 25. 48.The method of claim 46, wherein the host is a human.
 49. The method ofclaim 47, wherein the host is a human.
 50. A method for inhibitingreplication of a virus, which comprises contacting the virus with thecompound of claim
 1. 51. A method for inhibiting replication of a virus,which comprises contacting the virus with the pharmaceutical compositionof claim
 25. 52. A method for inhibiting the activity of a polymerase,which comprises contacting the polymerase with the compound of claim 1.53. A method for inhibiting the activity of a polymerase, whichcomprises contacting the polymerase with the pharmaceutical compositionof claim
 25. 54. The method of claim 52, wherein the polymerase is anHCV NS5B polymerase.
 55. The method of claim 53, wherein the polymeraseis an HCV NS5B polymerase.